Oh nh-cc



, wherein tP atented Fe, it i? t A. H. Frieeim, New York, N. Y.

No Drawing. Application Ant 27, 1942,

Serial No. d56,367

(ill.

This invention relates to therapeutically active I organic condensation products containing at least one 1,3,5-triazine ring and to the methods of preparing such condensation products. It has particular relation to organic-compounds which in addition to the l,3,5-triazine ring or rings contain cyclic sulionic acid radicals, and in which the link between the triazine ring and said radicals is formed by a system containing at least one cyclic organic radical carrying a divalent radical of an acid group, such as --'-C()-- or SO2, and an amino group. Both, the cyclic sulfonic acid radicals and the link-forming groups, may contain monocyclic or polycyclic, and isocyclic or heterocyclic radicals and. they may also contain various substituents.

The compounds according to this invention,

have the general formula In the above Formula I it represents a cyclic sulfonic acid radical which may contain substi tuting groups, such as those selected from the group consisting of OH, -O-alkyl, halogen, --NH-alkyl, NH-acyl, -CONH2, -SO2NH2. As examples of the formulas of the beiorementioned cyclic sulfonic acid radicals the following may be mentioned:

L stands for a cyclic, acid amide-containing link of the formula (NHR1 (Nil -R2) (NH-Ru) stand for identical or diflerent cyclic groups carrying identical or diflent acid amide groups, such as -CO-NH, -SQ2---, and

such acid amide groups being linked by their nitrogen atom to a nuclear carbon of the neighboring cyclic group. it is an integer preferably smaller than 4. Thus, R1, Ra etc, may represent the residue of benzoic amide, naphthoic amide, benzene sulfonamide, naphthalene sulfonamide, including their substitution products, such as those carrying alkyl, ow-alkyl, aminoalkyl, amino-acyl, halogen or nitro groups connected to the aromatic nuclei. As examples of the formulas of the groups (NHR1) etc.,

the following may be mentioned:

v NHC o-Q (NH-C 0G)- SOs-NH (I) AIR-cofigk In the above formulas n represents an inte er being at least 1, and the individual (NH-R) groups may be linked in similar or diflerent positions (ortho, meta, para) to each other.

Y and Z may be equal or diflerent and may represent halogens, or residues of any inorganic or organic, aliphatic or aromatic, monocyclic-or polycyclic, isocycllc or heterocyclic, molecule con-- taining a hydrogen atom capable oireacting with a cyanuric halide with elimination of a halogen halide. For example, Y and Z may be Cl, -Bl',

-NH-II-NH,, -NH(|INHCN residues of cyanamide derivatives, residues of substituted guanidines, metallic radicals, -SH,

alkyl radicals and their substitution products, and

isocyclic or heterocyclic hydrocarbon radicals, which may be monocyclic or polycyclic, and their substitution products, such as O-aryl groups, amino-aryl radicals, such as those corresponding to the formula wherein A and B may represent equal or diilerent substituent's, and E may represent a radical selected from the group consisting of -SO3H, SO2NH2, metallic radicals, and triazine radicals. All these radicals standing for X and/or Y, may be linked to the triazine ring carbon atom directly or indirectly, the link between X and Y and said ring carbon atom being formed in the latter case, I. e. by radicals of the formula Finally Y and/or Z may also stand for equal or different groups corresponding to the symbol A LNH or they may represent a group containing one or more triazine rings.

Preparation 01' compounds corresponding to the above general Formula I may be effected by reacting a compound of the formula A-L-W (referred to hereinafter as Formula II), with a 1,3,5-triazine compound or the formula Y- c-z I wherein W is halogen or an amino group and at least one of X, Y, Z is an amino group or halogen capable of reacting with W.

The resulting reaction products may, if so desired, and if they retain at least one halogen connected to a triazine ring carbon, be further treated with organic and inorganic compounds containing an active hydrogen atom capable of reacting withcyanuric halide with elimination of hydrogen halide. Such compounds are water, alcohols, phenols, naphthols, NHa, substituted primary aliphatic and cyclic amines, organic and inorganic compounds carrying .2. SH group, compounds of theformula AL-NH2, wherein these compounds may be the same as used in the first reaction stage, or different from the same. If a resulting reaction product contains an --NH: group attached to a triazine ring carbon, it may, it so desired, be reacted with any organic molecule capable of reacting with said amino group, such ,as a molecule of the formula A-L-W, wherein W is a halogen.

The compounds embodying the present invention present in the form of their sodium salts,

white or yellowish powders, soluble in water, in-

Formula 111, as suggested by E. Fourneau, Annales de lInstitut Pasteur, 1924, p. 108:

sour NH-C o-Qcm NH to One mol of 5% aqueous solution of the sodium salt of this compound (HI) containing one moi of sodium bicarbonate is poured slowly with emcient stirring and cooling into an ice-cold 10% suspension oi! one moi of cyanuric chloride in water. After all diazotable aromatic amine has.

disappeared from the reaction mixture, the reaction product is salted out, filtered oil and purilied by redissolving in water at slightly alkaline reaction (pH about 7.6) bone, blacking and filtering. The sodium salt of a compound corresponding to the following Formula IV is obtained in the form of a white-powder by salting out. filtration, washing with concentrated sodium acetate solution, alcohol and ether:

$0.21 NHC o-Qcrn NH to SOIH Compound IV may be reacted with ammonia in order to replace one or both Cl atoms by NH: groups, or it may be reacted with compound III in order to react one or both Cl atoms in compound IV with the active hydrogen atom of the free amino group of compound 111. If two Cl atoms of cyanuric chloride are replaced by the residue of compound III, the remaining Cl atom may be replaced by another radical, such as, for example, -NH2 or SH.

Example II .--Compound IV is dissolved in 10% aqueous ammonia at a temperature not exceed-v ing 30 C. After standing for about 6 hours, the excess of ammonia is eliminated under vacuum and a product corresponding to the. following Formula V is salted out, purified and isolated in the manner described in Example 1.

son: NHC o-Qom Example III.By treating compound IV as described in Example II, but using concentrated (III) 5. aqueous ammonia, andthe temperature of boiling water bath, both Cl-atoms of compound IV are replaced by NHz-gmups to form the compound corresponding to the following formula:

The same compound V1 is obtained by suspending 1.1 mol of 2,4-diamino-6-ehloro-1,3,5-trlazine in a aqueous solution of one mol of compound IH, said solution also containing 1 mol of sodium acetate, and boiling the reaction mixture with stirring and refluxing until a clear solution is formed, and all diazotable aromatic amine has disappeared. Compound VI thus formed is isolated and purified substantially in the manner described in Example I.

Example IV.A 5% aqueous solution of 2 mols' of the sodium salt of compound III, containing 2 mols of sodium bicarbonate, is slowly introduced with efilcient stirring into an ice-cold suspension of 1 mol of cyanui'ic chloride in water. The temperature is kept below 5 C. until the first half of .the solution is introduced, and alsoil! v lowed then to rise to room temperature but not The same compound may be Prepared by treating a solution of the sodium salt of compound IV with an equimolecular quantity of the sodium salt of compound III. The chlorine atom in the triazine ring of compound VII may be substituted by -NH2 by boiling compound VII with concentrated ammonia. It may also be substituted by the residue of compound in by refluxing an aqueous solution of the sodium salt of compound VII with an equimolecular quantity of the sodium salt of compound III. Com= pound VII may thus be prepared with or without isolation of the intermediate product corresponding to Formula IV. The C1 atom in the trlazine ring of compound VH may also be replaced by SH, by treating compound VII with hot concentrated NaSH solution.

Example V.--A 5% aqueous solution 0! 3 mole of the sodium salt of compound DI, containing 3 mols or sodium bicarbonate is slowly introduced with eflicient stirring to an ice-cold 10% suspension of one mol of cyanuric chloride in water. The temperature is so regulated that one third of the sulfonic acid solution is introduced at a temperature not exceeding 5 C. The temperature is then allowed to rise to room. temperature, and after all sulfonlc acid has been added. stirring is continued on the boiling water bath until all diazotable aromatic amine has disap- I peared. The new compound is then salted out, isolated and purified in the manner described in Example I. It has the following formula:

sour

OaH NH-t t-Ns v Compound VIII can also be prepared from the over 30 C. Stirring is continued. until all diintermediate compounds corresponding to Forazotable aromatic amine has disappeared from the reaction mixture. The compound formed is salted out, isolated and purified as in Example I, and has the following Formula VII:

SOaH

mulas IV and VII.

In Examples 111 to V, 1,4,8-naphthylamine disulfonic acid may be used in place of 1,43,8- naphthylamine trisulfonic acid.

Example VI.A compound (IX) of the for- Example VIII.-1 moi of the sodium salt of'the mula, compound IV is dissolved in water and treated on NH CO (IX) on the water bath with 3 mols of NaSH in concentrated aqueous solution. The reaction is com- I NH-CO 5 pleted when all chlorine in the reaction mixture Q is present in the ionized form. The reaction prod NH uct is salted out, isolated and purified as in Example I, but following the washing with alcohol is prepared in a known manner (see U. S. Patent wlth alcohol and ether It has the No. 1,308,071, issued on July 1, 1919). One mol mula of this compound, in mixture with 1 mol of so- N -co on, dium bicarbonate, is added in a concentrated aqueous solution of its sodium salt, slowly and NH to $01K SOsH- $0311 with good stirring to 1 mol of a 5% aqueous solution of compound IV. Stirring is continued at a temperature ranging between and C. until CL (x111 all diazotable aromaticamine has disappeared soda If N NHJ? from the reaction mixture. The compound IL formed is salted out of the reaction mixture,

and isolated and purified as in Example I. It 29 represents an asymmetrically substituted triazine Ew mple IX-1 mol of the sodium salt of comof the Formula X. pound VII, in 5% aqueous solution, is treated on 011000-13! BOaH NH on NH-CO- Cl do I v 5 S0311 NH-CO (X) Example VII .The halogen in the triazine ring the water bath with 2 mols of NaHS in concenof compound X may be substituted by refluxing trated aqueous solution until all chlorine of the one molecule of a solution of the sodium salt reaction mixture is in ionized form. The new of compound X with a moiecukof the sodium compound, which may be salted out and purified salt of compound III or IX, or another compound in the manner described in Example VJJI, has corresponding to the formula A(NHR) NH2, the Formula XIV.

' (xiv soar NH-C o-Q-cm cm-Qco-mn SIQsH 1 1a. Em

(:0 sn 0 sea a v I sou;

. a 01H 1|\|X/ \N 0 -SOaH NH-O -Ns a such as, for example, a compound of the formula Example X.-0ne part of the sodium salt of so compound XIV is dissolved in 20 parts of water. I T Q The solution is adjusted to a reaction just alkaline NH, (XI) to phenolphthaleine, and mixed with a twofold excess of dilute (2%) H202. After standing for 24 SOaH 302E hours at room temperature, a trace of catalese is added and a reaction product corresponding to to form the following compound (XII) Formula XV is salted out and purified as in Exsoul sous SOs-NH H a CBp-O-CQ-NH sod: x11) NE NE on NE-CO to I SOIH n-ooQ N SOaH SOaE NH-C l ample I. The compound thus formed has the appeared fromthesolution. The product formed formula: (XVII) is salted out, isolated and purified in the sour NH-OOQOH. on oo-nn sea I to 150mm 03H on O L our 1 .NH N NE I Ii 0 L (xv sou-1 Nn-coqcm o (JO-NH sous l n 50 A o SOiH 5 NH- o-Nn This process allows the preparation of condenmanner described in Example I. It has the forsation products containing more than one triazine mul'a: ring and showing a symmetry of structure relative to 2 planes.

By proceeding in analogous way, triazine disul Nil-c0 fldes may be obtained, showing only a simple symmetry relative to one plane. By treating, for H example, compound V in an analogous manner,

' o the following triazine dlsulflde (XVI) may be 30in obtainedzle I m N Emmp x 4o NH--E/ C-NHa I p I I, I\?/ I NH sou: NH -OOQOIH r v v x 80:11

50.: it 01H N sous: Nn-oo-Q-cm I NH-C (J-NH: NH 0:11

5- 0 NE 50.2! NH-OO on. (i SOsH I (\J v NH H OH I r/ \N 80m to Nn-(': -Nn:

OaH

(XVII N NIH- -NH:

Example XML-2 mols of the sodium salt of a compound of the Formula xvm.

on NH-CO-CH =CH-C v 7 NH: Example XII.-2 mols of the sodium salt of compound V are dissolved in 20 parts of water H containing 2 mols of sodium acetate, and 1 mol oi the disodium salt ofv benzicline 3,8"--disulf01nlc 801E (XVIII) acid. The reaction mixture is boiled with refluxlng until all dlazotable aromatic amine has disprepared accordin to; 'U. 58., Patent 1,308,071;

it issued on July 1, 1919, dissolved in 10 parts of water containing 2 mols of sodium bicarbonate are run slowly with stirring into a cold 10% aqueous suspension 01' 2-amino-4,6-dichloro-1,3,5 triazine. The temperature is raised slowly to boiling and stirring is continued until all diazotable amine has disappeared. The new compound (XIX) is salted out, isolated and purified in the on NIP-COQO cm NHC OQCH: soul N I 2} N H-SO N Hi NBC-( l g-NH V Example XI V.---A compound of the formula:

SOIH. NH-OGH=CH QOzH is prepared according to standard methods outlined in Example I, and is used to replace one, two or three Cl atoms in cyanuric chloride. The reaction is carried out substantially in the manner described in the foregoing examples.

Example XV.--2 mols oi the sodium salt oi a compound xxx of the formula:

on NH-C o-Q-ocm NH-COQ-OOH:

08H prepared as described in U. S. Patent N 0. 1,308,071 dissolved in 10 parts of water containing 2 mols N mg is 12 of sodium acetate are run slowly with stirring into an ice-cold 10% suspension of cyanuric bromide. Stirring is continued while the temperature is slowly raised to the boiling point, until all diazotable amine has disappeared from the reaction mixture. The new compound (m) is salted out. isolated and purified in the manner described in Example I. It has the formula:

CHaO r O0 O-NH on 0-NIl our oi n XII) Example XVI..By reacting one mol. of 7- amino-B-methyl-chinoline-S-sulfonic acid with one mol of l-nitro-naphthalene-5-sulfochlorlde and subsequent reduction of the reaction product the following substitution product is obtained:

503E NO;

NE N By reacting two mols of the sodium salt of this substitution product with one moi of cyanuric chloride in a manner analogous to that described in the preceding examples a compound of the following formula is obtained:

Example XVIL-A condensation product is prepared by reacting one moi of 1, 3, 5-anilinedisulfonic acid with one mol of chinoline-5-nitro- 2-carbonyl chloride and subsequent reduction:

80,11 NO I S083 NH: 0100 N soln NH.

so H NH-CO Two mols of the sodium salt of this new product are reacted with one mol of cyanuric chloride substantially in a manner analogous to that described in the preceding examples. The con- Or-NH' '14 densation product thus formed has the following suspension of cyanuric chloride in the presence formula: of alkali biacrbonate.

N/ x l 7 sons NH- C-NH 80,11

N SOaH NH-CO N (JO-NBQSOQI Various modifications and variations of the in- 3. An organic compound corresponding to the vention, as hereinbefore set forth, may be made general formula without departing from the spirit and scope thereof, and therefore, only such limitations should be imposed as are included in the apfig soda NH-COQ-CH; 1. A new 1, 3, 5-triazine compound consisting l of a 1, 3, 5-triazine ring, at least one ring carbon E atom of which is directly linked to a radical of 80m 0 Y! the formula Y wherein Y and Z represent radicals selected NH-- from the group consisting of halogens and NH2. 4. An organic compound corresponding to the while remaining carbon atoms are connected to formula son: r m-co on. CHrQCQ-IIIH sour 113 I if! V i o 01 sous l I o om 0.11 1 I \N SOaH NH-o Jl-NH radicals selected from the group consisting of 5. An organic compound corresponding to the halogens and NHa. formula son! NH-COQCH: on co-m: coir!- in: a 5 11H o 0 N/ \N son;

2. A process for obtaining condensation products containing a 1, 3, 5-triazine ring carrying at ERNST A. H. FRIEDHEIM. least one residue of the compound I 1 REFERENCES CITED sou: nn-ooQ-om The following references are of record in the NH J 05 file of'this patent: I $0 UNITED STATES PATENTS Number Name Date 2,306,439 Hentrich Dec. 29, 1942 1,625,531 Fritzsche Apr. 19, 192'! NH: 1,625,533 Fritzsche Apr. 19, 1927 1,625,532 l ritzsche Apr. 19, 1927 said process comprising refl fl E an aq e u solution of said compound with an aqueous 

